Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions
| العنوان: | Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions |
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| المؤلفون: | Sanjeev Gupta, Karolina Pakos-Zebrucka, Peter Vandenabeele, Susan E. Logue, Mathieu J.M. Bertrand, Afshin Samali, Svetlana Saveljeva, Shane Deegan |
| المصدر: | Autophagy |
| بيانات النشر: | Informa UK Limited, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | endoplasmic-reticulum stress, Fas-Associated Death Domain Protein, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, ATG, autophagy related, chain, DDIT3, DNA-damage-inducible transcript 3, Endoplasmic Reticulum, Autophagy-Related Protein 7, caspase-8, Autophagy-Related Protein 5, cytochrome-c, FADD, Fas (TNFRSF6)-associated via death domain, Mice, 0302 clinical medicine, HSPA5, heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa), MOMP, mitochondrial outer membrane permeabilization, FADD, Endoplasmic Reticulum Chaperone BiP, Caspase, TNF, tumor necrosis factor, Caspase 8, 0303 health sciences, biology, Caspase 3, MEFs, mouse embryonic fibroblasts, BCL2, B-cell CLL/lymphoma 2, apoptosis, BAK1, BCL2-antagonist/killer 1, unfolded protein response, Caspase 9, Mitochondria, Cell biology, BAX, BCL2-associated X protein, autophagic cell death, 030220 oncology & carcinogenesis, endoplasmic reticulum stress, Tm, tunicamycin, roles, Microtubule-Associated Proteins, PARP, poly (ADP-ribose) polymerase, Signal Transduction, DISC, death inducing signaling complex, autophagy, Programmed cell death, Basic Research Papers, assays, caspase, fadd, ATG5, PBS, phosphate-buffered saline, ER, endoplasmic reticulum, PI, propidium iodide, 03 medical and health sciences, Animals, Humans, Molecular Biology, 030304 developmental biology, Bcl-2 family, Cell Biology, Fibroblasts, cell-death, Enzyme Activation, MAP1LC3 (LC3), microtubule-associated protein 1 light chain 3, HEK293 Cells, Gene Expression Regulation, DTT, dithiothreitol, TNFSF10, tumor necrosis factor (ligand) superfamily, member 10, Tg, thapsigargin, biology.protein, activation, bcl-2 family |
| الوصف: | Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells. |
| تدمد: | 1554-8635 1554-8627 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2f28c796284ac70d3b03988c7d028edTest https://doi.org/10.4161/15548627.2014.981790Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c2f28c796284ac70d3b03988c7d028ed |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548635 15548627 |
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